Quinine-aminophylline composition for muscle cramp therapy



United States Patent p I 2,9ss,sss 7 p QUINlNE-AMINOPHYLLINE comosmoN For:

MUSCLE CRAMP THERAPY. a William Bryant Rawl's, 136 57tlrSt., New York, NY. No Drawing. Filed Feb. 27, 1959; Ser. No. 795,927

6'Claims. Cl. 167-67) This invention relates to a new composition of matter for the control of muscle cramps.

Muscle cramps, which are prolonged, painful and involuntary contractions of the muscles, frequently appear as a satellitic symptom in rheumatic, peripheral vascular and metabolic diseases. For example, patients may be awakened by severe cramps several times each night, depending upon the severity of the disease, and are forced to massage the cramped muscle, stand or walk or employ other means to relieve the pains. These cramps usually increase in frequency and severity with the passage of time. Such etiological factors as cold, a sudden sharp blow, stagnation of the blood from prolonged standing and excess loss of salt by perspiration also tend to induce muscular cramps. Patients with rheumatoid arthritis also experience muscle stiffness, soreness and cramping at night; and the composition of the present invention relieves these symptoms in many instances.

The fundamental origin of muscle fasciculation and muscle cramps is not understood; but any condition which reduces the permeability and thereby the polarization of a muscle cell membrane may give rise to these phenomena. Electrical activity occurring in the fasciculations is believed to spread by continuity to adjacent muscle fibers until a major part of all the muscle is involved in a painful sustained contraction. The exact reason for this propagation from one muscle fiber to another is not clear, though electrolyte imbalance may be a possible explanation. There is evidence to indicate that increased muscle responsiveness or cramps may be due to a decrease in the ratio of the intracellular to the extracellular potassium concentration, resulting in hypopolarization of the membrane.

Quinine is believed to exert a competitive blocking of the action of acetyl choline upon the cell membrane at the myoneural junction and thus reduces the irritability of the nerve-muscle unit. Quinine is also thought to cause an intracellular migration of potassium, thereby increasing the degree of polarization and the ratio of the intracellular to the extracellular potassium, thus rendering the muscle cell less excitable. Quinine, nicotinic acid preparations, antihistamines and other drugs have been used to control the frequency and the severity of muscle cramps; but none of these have proven to be consistently effective.

Unexpectedly it was discovered that when certain xanthines such as aminophylline were administered with quinine in the manner described hereinafter, these muscular cramps could be prevented and relieved. The reason why this particular combination of drugs is so highly effective is not clear. Aminophylline itself has no known electrolytic efiect at the level of the neuromuscular unit directly. Experiments have shown that while it increases urinary flow, it does not significantly disturb the electrolyte balance. A consideration of the other known physiological activities of aminophylline shows that it alfects such functions as respiration, blood flow, elimination of carbon dioxide and other waste products from the cell of the aminophylline.

2,985,558 Patented May 23, 1961 ice metabolism and the overall nutrition of the cell; but the exact role it plays in the synergistic action with quinine in preventing and controlling muscle spasm is not clearly understood.

The new composition of thepresent invention comprises quinine or quinine derivatives having the physiological activity of quinine and aminophylline or other physiologically related xanthine, preferably in dosage unit forms. A preferred composition is approximately 3 parts by weight of aminophylline for--each-4 parts by weight of quinine; -However, these proportions may vary somewhat; for instance, from about 2 parts by weight to 10 parts by weight of quinine for each 3 parts by weight The preferred unit dosage. 'contains about 3 grains of the aminophylline and 4 grains of quinine in a scored tablet so that smaller doses of from about 1.5 grains of aminophylline to 2 grains of quinine may be taken at one time if desired. It will be understood, of course, that these dosage forms may be smaller or larger for particular purposes. For instance, a smaller tablet may be used for treating children and a larger tablet for treating large animals.

Ordinarily one tablet is administered to a patient by the oral route just prior to retirement since muscular spasm occurs most frequently while the patient is in a reclining position. In more severe cases where muscular spasm occurs during the I daytime, as many as three of the tablets containing 3 grains of aminophylline and 4 grains of quinine may be administered at appropriately spaced intervals. However, such treatment should not be continued more than four or five days without advice of the attending physician.

It will be understood that the composition described is not a cure for the condition which causes the muscle cramps. It merely relieves or prevents their occurrence. However, dosage may be discontinued in some cases for several weeks without recurrence of the spasms. Removal of the cause of the spasm will, of course, make it possible to discontinue medication for longer periods of time.

Although it is preferred that the composition be administered in tablets as just described, the powdered mixture may be filled into gelatin capsules, made into granules or incorporated in a syrup or elixir in liquid form for convenient oral administration. It is even possible to prepare and administer the composition by the intramuscular route. Larger quantities of the drug are usually required in such instances.

Example Two hundred sixty grams of quinine and grams of aminophylline are intimately mixed with 50 grams of corn starch and 350 grams of lactose. The mixed powders are granulated with a 5 percent starch paste and forced through a l2-mesh stainless steel screen. The granulation is dried thoroughly at a temperature of 35 C. and then forced through a l6-mesh steel screen. Ten grams of talc and 4.5 grams of magnesium stearate are added and mixed by tumbling with the granulation. The granulation is then compressed into 1000 tablets, each tablet containing 4 grains of quinine and 3 grains of aminophylline.

I claim:

1. A composition of matter for the control of involuntary muscle spasms which comprises a mixture of therapeutically effective amounts of quinine and aminophylline.

2. A composition of matter for the control of involuntary muscle spasms which comprises 3 parts of aminophylline and 2 to 10 parts by weight of quinine.

3. A composition of matter for the control of involuntary muscle spasms whichcomprises in dosage unit form a mixture of from 1 to 4 grains of aminophylline with I to 10 grains of quinine.

'4.. A composition of matter for the control ofinvoluntary muscle spasms which comprises indosage unit form approximately 3 grainsof aminophylline and 4 grains of quinine.

5. A method of controlling involuntary muscle spasms 1 which comprises orally administering aminophylline. and quinine in therapeutically efiective amounts. a

r 6. A method of controlling involuntary muscle spasms which comprises'administering a quantity of about 3 grains of aminophylline and 4 grains-of quinine.

References Cited in the file of this patent UNITED STATES PATENTS 1 2,752,285 Weissenburger et a1. June 26, 1956 4 FOREIGN PATENTS Great Britain Feb. 31900 OTHER REFERENCES Remingtons Practice of Pharmacy, l lth ed., 1956, p.

Goodman et al.: Pharmacological Basis of Therapeutics, pp. 339-353, esp. pp. 3l45-346r Lesser: Drug and Cosmetic Industry, .March 1950, 66: '3, pp.-276, 277, 340, 342, 343,, 3.45. a

U.S. Dispensatory 25 1957, pages 1410-1411; 

1. A COMPOSITION OF MATTER FOR THE CONTROL OF INVOLUNTARY MUSCLE SPASMS WHICH COMPRISES A MIXTURE OF THERAPEUTICALLY EFFECTIVE AMOUNTS OF QUININE AND AMINOPHYLLINE. 